PROJECT SUMMARY The objective of our program is to develop a safe and effective therapeutic for chronic cough. Chronic cough, or cough that persists for more than eight weeks, is a condition that is often associated with diseases such as chronic obstructive pulmonary disorder (COPD), asthma, idiopathic pulmonary fibrosis, bronchiectasis or gastroesophageal reflux disease (GERD). In other cases, the etiology is unknown. Chronic cough has significant physical, psychological, social and economic consequences that negatively impact quality of life. Prevalence in the United States is as high as 11%, and in a majority of cases the condition is refractory. Compelling evidence supports the hypothesis that chronic cough arises from alterations in sensory physiology that cause hypersensitivity to previously innocuous stimuli. The voltage-gated sodium ion channel Nav1.7 is highly expressed in unmyelinated vagal nerve afferents that trigger cough through a sensorimotor reflex circuit. Results from a published pre-clinical report show that reducing expression of Nav1.7 nearly abolishes cough evoked by inhaled irritants, indicating that it is a promising target for reducing cough. SiteOne Therapeutics has discovered potent and selective small molecule inhibitors of Nav1.7 that block vagal C-fiber activity in a dose-dependent manner. The Aims of this Phase I project are to evaluate a series of Nav1.7 inhibitors against physiological, pharmacokinetic, and efficacy endpoints in order to demonstrate the feasibility of developing a therapeutic candidate for chronic cough and to select a candidate for nonclinical development.